The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors

Repair of topoisomerase 1–induced DNA damage by tyrosyl-DNA phosphodiesterase 2 (TDP2) is dependent on its magnesium binding

“…Focusing on the broad substrate spectrum of TDP2, the inhibition of TDP2 is an attractive target for tumor cell sensitization in combination with TOP1 inhibitors and CTNAs. Some studies have reported the development of specific TDP2 inhibitors, which include deazaflavin ( 56 , 57 , 58 , 59 ), isoquinoline-1,3-dione ( 60 ), furoquinoline ( 61 ), diaminoquinoline-2,8-dione ( 62 ), and isoxazoloquinolinedione ( 63 ). In addition, the derivatives of indenoisoquinoline were found to be triple TOP1–TDP1–TDP2 inhibitors ( 64 ).…”

New Indole Diketopiperazine Alkaloids from Soft Coral‐Associated Epiphytic Fungus Aspergillus versicolor CGF 9‐1‐2

“…TDP is tyrosyl-DNA phosphodiesterase, TDP1 and TDP2 are members of the phospholipase D superfamily, they are two DNA repair enzymes, which have the ability to hydrolyze the tyrosyl-phosphodiester bond of the phenol of tyrosine with 3'and 5'-DNA end, respectively, and contained in the metabolites of the damaged DNA mediated by topoisomerase 1 and 2, the abnormal activation and expression of TDP1 or TDP2 is the important reason for cancer development. [17][18] Therefore, TDP1 and TDP2 are regarded as a promising therapeutic target to enhance established cancer treatment. [19] As a part of our continuing research on novel bioactive secondary metabolites from soft coral-derived fungus A. versicolor CGF 9-1-2, [20][21][22][23] fifteen IDAs were isolated from the ethyl acetate (EtOAc) extract, including two new ones, and 13 known analogs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”